Otevřená farmakokinetická studie formulací ASP-001 u zdravých dobrovolníků

Inclusion Criteria:

1. Male or female, ≥18 and ≤65 years of age at screening, with body mass index (BMI) ≥18.5 and ≤32.0 kg/m2 and body weight ≥50.0 kg for males and ≥45.0 kg for females.

2. Healthy as defined by:

   1. the absence of clinically significant illness and surgery (including abdominal or gastrointestinal surgery that may alter drug absorption) within 4 weeks prior to dosing.
   2. the absence of clinically significant history of neurological (including Parkinson's disease or other extrapyramidal disorders), endocrine, cardiovascular, respiratory, hematological, immunological, psychiatric (including depression), gastrointestinal, renal, hepatic, and metabolic disease.

3. Non smoker, defined as no use of tobacco or nicotine containing products (including cigarettes, e cigarettes, cigars, pipes, or smokeless tobacco) for at least 6 months prior to screening.

4. Female participants of non-childbearing potential must be:

   1. post-menopausal (spontaneous amenorrhea for at least 12 months prior to dosing) with confirmation by documented follicle stimulating hormone (FSH) levels ≥40 mIU/mL; or
   2. surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy) or having had a tubal ligation performed at least 3 months prior to dosing.

5. Sexually active female participants of childbearing potential and non-sterile male participants must be willing to use an acceptable contraceptive method throughout the study as detailed in section 7.1.

6. Willing to take off dentures or mouth piercing at the time of dosing.

7. Able to understand the study procedures and provide signed informed consent to participate in the study.

Exclusion Criteria:

1. Any clinically significant abnormal finding at physical examination at screening.

2. PHQ-9 score > 10 at screening or baseline (Day -1).

3. Clinically significant abnormal laboratory test results or positive serology test results for HBsAg, HCV antibody, or HIV antigen and antibody at screening. Any abnormalities or deviations outside the normal ranges for any clinical laboratory testing can be repeated once at the discretion of the investigator and/or designee.

4. Any of the following laboratory parameters above 1.5× upper limit of normal (ULN) at screening or baseline (Day -1): AST, ALT, direct bilirubin, indirect bilirubin, and total bilirubin. Values over 1.5× ULN may be repeated once for confirmation if the investigator considers it reasonable (e.g., potential elevation due to recent strenuous physical activity).

5. History of clinically significant liver disease, impaired synthetic liver function, or jaundice. Resolved childhood jaundice is not exclusionary.

6. Value of creatinine clearance (CrCl) <60 mL/min, as estimated by the Cockcroft-Gault equation.

7. Positive pregnancy test or lactating female participant.

8. Positive urine drug screen, urine cotinine test, or alcohol breath test.

9. Known allergic reactions to flunarizine or other related drugs, or to any excipient in the formulation.

10. Clinically significant ECG abnormalities or vital signs abnormalities (systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 40 or over 90 mmHg, or heart rate less than 40 or over 100 bpm) at screening. Any abnormalities or deviations outside the normal range for vital signs and ECG can be repeated at the discretion of the investigator and/or designee.

11. History of drug abuse within 1 year prior to screening or recreational use of marijuana within 1 month, or use of cocaine, phencyclidine [PCP], crack, opioid derivatives (including heroin) or amphetamine derivatives within 3 months prior to screening.

12. History of alcohol abuse within 1 year prior to screening or regular use of alcohol within 6 months prior to screening that exceeds 14 standard drinks for females or 21 standard drinks for males of alcohol per week (1 standard drink = 375 mL of mid-strength beer 3.5% alcohol/volume, 100 mL of wine 13.5% alcohol/volume, or 30 mL of distilled alcohol 40% alcohol/volume).

13. Use of medications within the the following timeframes prior to dosing:

    • Depot injections or drug implants: within 3 months.
    • Strong CYP2D6 inhibitors or strong CYP inducers such as fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, terbinafine, mirabegron, darifenacin, rifampin, carbamazepine, phenytoin, phenobarbital, and St. John's wort: within 30 days.
    • Prescription medications: within 14 days.
    • Vaccines (including COVID 19 vaccines): within 14 days.
    • Over the counter (OTC) medications and natural health products (herbal, homeopathic, probiotics, vitamins, minerals, amino acids, essential fatty acids, protein supplements): within 7 days, except occasional paracetamol up to 2 g/day.

    No concomitant medications are permitted during the study except those required for AE management or those specifically exempted by the Investigator and/or designee as unlikely to affect PK or safety.

14. Concomitant participation in an interventional or observational trial, or administration of an investigational device or non-biological drug within 30 days (or 5 half-lives, whichever is longer) prior to dosing, or administration of an investigational biological drug within 90 days (or 5 half-lives, whichever is longer) prior to dosing.

15. Donation of plasma within 7 days prior to dosing or donation or loss of 500 mL or more of whole blood within 8 weeks prior to dosing.

16. Hemoglobin <125 g/L for males and <110 g/L for females. One repeat test is permitted at the discretion of the Investigator and/or designee.

17. Presence of orthodontic braces or orthodontic retention wires, or any physical findings in the mouth or tongue that in the opinion of the investigator and/or designee would be likely to interfere with successful completion of the dosing procedure.

18. Any reason which, in the opinion of the Investigator and/or designee, would prevent the participant from participating in the study.